PMID- 30044964
OWN - NLM
STAT- MEDLINE
DCOM- 20190415
LR  - 20220330
IS  - 1878-5875 (Electronic)
IS  - 1357-2725 (Linking)
VI  - 102
DP  - 2018 Sep
TI  - Upregulation of EphB3 in gastric cancer with acquired resistance to a FGFR 
      inhibitor.
PG  - 128-137
LID - S1357-2725(18)30158-4 [pii]
LID - 10.1016/j.biocel.2018.07.008 [doi]
AB  - Amplification of fibroblast growth factor receptor2 (FGFR2) has been regarded as 
      a druggable target in gastric cancer (GC). Despite known potential of AZD4547, a 
      selective inhibitor of FGFR 1-3, to suppress tumorigenic effects of activated 
      FGFR2, resistance to the targeted agent has been an unresolved issue. This study 
      was performed to elucidate the mechanism of AZD4547 resistance in GC cells. 
      SNU-16 cells were used to establish an AZD4547-resistant GC cell line, SNU-16R. 
      Elevated phosphorylation of EphB3 was confirmed using the Human Phospho-Receptor 
      Tyrosine Kinase Array kit. A tyrosine kinase inhibitor (TKI) of EphB3 was used to 
      investigate the effects of suppressed EphB3 activity in the SNU-16R cell line. 
      SNU-16R cells exhibited upregulated phosphorylation of EphB3. Treatment of 
      SNU-16R cells with the EphB3 TKI resulted in induction of apoptosis, decreased 
      cellular viability, and cell cycle arrest at sub-G1 phase. SNU-16R cells 
      expressed upregulated levels of N-cadherin, vimentin, Snail, matrix 
      metalloproteinase 2 (MMP-2), and MMP-9, and reduced levels of E-cadherin, 
      characteristic of epithelial to mesenchymal transition (EMT). Matrigel invasion 
      assay also demonstrated the increased invasiveness of SNU-16R cells. EphB3 TKI 
      treatment inhibited EMT of SNU-16R cells. Activation of mammalian target of 
      rapamycin (mTOR) through the Ras-ERK1/2 pathway was suggested as the signal 
      transduction mechanism downstream EphB3 by showing enhanced phosphorylation of 
      Raf-1, MEK1/2, ERK1/2, mTOR and its downstream substrates in SNU-16R cells. As 
      expected, EphB3 TKI decreased phosphorylation of these proteins. Our data suggest 
      phosphorylation of mTOR through signaling by EphB3 is a potential mechanism of 
      AZD4547 resistance in GC cells.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Lee, Suk-Young
AU  - Lee SY
AD  - Division of Oncology/Hematology, Department of Internal Medicine, College of 
      Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of 
      Korea. Electronic address: totokee777@naver.com.
FAU - Na, Yoo Jin
AU  - Na YJ
AD  - Division of Oncology/Hematology, Department of Internal Medicine, College of 
      Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of 
      Korea. Electronic address: wing1278@naver.com.
FAU - Jeong, Yoon A
AU  - Jeong YA
AD  - Division of Oncology/Hematology, Department of Internal Medicine, College of 
      Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of 
      Korea. Electronic address: leomi2614@naver.com.
FAU - Kim, Jung Lim
AU  - Kim JL
AD  - Division of Oncology/Hematology, Department of Internal Medicine, College of 
      Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of 
      Korea. Electronic address: clickkjl@naver.com.
FAU - Oh, Sang Cheul
AU  - Oh SC
AD  - Division of Oncology/Hematology, Department of Internal Medicine, College of 
      Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of 
      Korea. Electronic address: sachoh@korea.ac.kr.
FAU - Lee, Dae-Hee
AU  - Lee DH
AD  - Division of Oncology/Hematology, Department of Internal Medicine, College of 
      Medicine, Korea University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of 
      Korea; Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea 
      University, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea. Electronic 
      address: humyam@daum.net.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180722
PL  - Netherlands
TA  - Int J Biochem Cell Biol
JT  - The international journal of biochemistry & cell biology
JID - 9508482
RN  - 0 (AZD4547)
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - EC 2.7.10.1 (FGFR2 protein, human)
RN  - EC 2.7.10.1 (Receptor, EphB3)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Benzamides/pharmacology
MH  - Cell Line, Tumor
MH  - *Drug Resistance, Neoplasm
MH  - Epithelial-Mesenchymal Transition/drug effects
MH  - Humans
MH  - Phosphorylation/drug effects
MH  - Piperazines/pharmacology
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyrazoles/pharmacology
MH  - Receptor, EphB3/*metabolism
MH  - Receptor, Fibroblast Growth Factor, Type 2/*antagonists & inhibitors
MH  - Signal Transduction/drug effects
MH  - Stomach Neoplasms/*pathology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Up-Regulation/*drug effects
OTO - NOTNLM
OT  - EphB3
OT  - FGFR inhibitor
OT  - Gastric cancer
OT  - Resistance
OT  - mTOR
EDAT- 2018/07/26 06:00
MHDA- 2019/04/16 06:00
CRDT- 2018/07/26 06:00
PHST- 2018/03/13 00:00 [received]
PHST- 2018/07/20 00:00 [revised]
PHST- 2018/07/21 00:00 [accepted]
PHST- 2018/07/26 06:00 [pubmed]
PHST- 2019/04/16 06:00 [medline]
PHST- 2018/07/26 06:00 [entrez]
AID - S1357-2725(18)30158-4 [pii]
AID - 10.1016/j.biocel.2018.07.008 [doi]
PST - ppublish
SO  - Int J Biochem Cell Biol. 2018 Sep;102:128-137. doi: 10.1016/j.biocel.2018.07.008. 
      Epub 2018 Jul 22.